The broad, long-term objectives and specific aims are to increase hematopoietic cell donor availability, progression free and overall survival following allogeneic hematopoietic cell transplantation (HCT) for malignant diseases. One major obstacle for HCT is the lack of a suitable donor. We have developed a non myeloablative regimen that is the first step or platform in a process of graft engineering that will allow us to add other building blocks for a more successful graft. Our results suggest that this alemtuzumab based non myeloablative regimen allows engraftment with low morbidity and treatment related mortality, allowing older, more infirmed patients to undergo allogeneic HCT. The primary limitations to greater success are relapse and delayed immune recovery. The central hypothesis of this project is that we will be able to engineer a graft that allows engraftment without graft versus host disease (GVHD). We will then build in a post transplant strategy to enhance anti tumor responses. Several complementary projects will be pursued in order to test this hypothesis. In the first aim, we will complete the feasibility study and early immune reconstitution analyses to provide a foundation and then focus on a larger phase II study enrolling better risk patients to confirm our initial observations. This aim will be the foundation for the additional graft enhancements in Aims 2-4 and projects I, II, and III. In Aim 2, we will continue our initial studies of addition of donor natural killer cell (NK) infusions following HCT and monitor immune responses against the tumor and overall immune recovery. Aim 3 will begin our first series of studies using WT-1 as a target in hematolymphoid diseases. This first study of WT-1 will be the foundation for us to build upon additional strategies aimed at this tumor specific antigen. Aim 4 will be to carry out a clinical study with the use of TLR ligands (initially CpG) along with Project III. This project will also serve as the information center for the early phase I studies that will be carried out in Project II. Each clinical study is supported by Cores A & B. The correlative analyses from each study are supplied by Core C. Thus this project serves as the clinical research for the other projects and interacts extensively with all three cores. The lessons learned from these trials will set the stage for future studies aimed at decreasing GVHD and relapse and improving long term survival.